title: Zfat-deficiency results in a loss of CD3ζ phosphorylation with dysregulation of ERK and Egr activities leading to impaired positive selection.
abstract: The human ZFAT gene was originally identified as a susceptibility gene for autoimmune thyroid disease. Mouse Zfat is a critical transcriptional regulator for primitive hematopoiesis and required for peripheral T cell homeostasis. However, its physiological roles in T cell development remain poorly understood. Here, we generated Zfat (f/f)-LckCre mice and demonstrated that T cell-specific Zfat-deletion in Zfat (f/f)-LckCre mice resulted in a reduction in the number of CD4(+)CD8(+)double-positive (DP) cells, CD4(+)single positive cells and CD8(+)single positive cells. Indeed, in Zfat (f/f)-LckCre DP cells, positive selection was severely impaired. Defects of positive selection in Zfat-deficient thymocytes were not restored in the presence of the exogenous TCR by using TCR-transgenic mice. Furthermore, Zfat-deficient DP cells showed a loss of CD3ζ phosphorylation in response to T cell antigen receptor (TCR)-stimulation concomitant with dysregulation of extracellular signal-related kinase (ERK) and early growth response protein (Egr) activities. These results demonstrate that Zfat is required for proper regulation of the TCR-proximal signalings, and is a crucial molecule for positive selection through ERK and Egr activities, thus suggesting that a full understanding of the precise molecular mechanisms of Zfat will provide deeper insight into T cell development and immune regulation.
authors.affiliation: Department of Cell Biology, Faculty of Medicine, Fukuoka University, Jonan-ku, Fukuoka, Japan ; Central Research Institute for Advanced Molecular Medicine, Fukuoka University, Jonan-ku, Fukuoka, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ogawa
authors.forename: Tadashi
authors.initials: T
authors.lastname: Okamura
authors.forename: Shuhei
authors.initials: S
authors.lastname: Ishikura
authors.forename: Keiko
authors.initials: K
authors.lastname: Doi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsuzaki
authors.forename: Yoko
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Takeharu
authors.initials: T
authors.lastname: Ota
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Hayakawa
authors.forename: Harumi
authors.initials: H
authors.lastname: Suzuki
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Tsunoda
authors.forename: Takehiko
authors.initials: T
authors.lastname: Sasazuki
authors.forename: Senji
authors.initials: S
authors.lastname: Shirasawa
mesh_terms: D000818:Animals; D017252:CD3 Complex / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D060966:Clonal Selection, Antigen-Mediated / Q000235:genetics* / Q000276:immunology*; D051765:Early Growth Response Transcription Factors / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005786:Gene Expression Regulation; D016130:Immunophenotyping; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D060168:Thymocytes / Q000166:cytology / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
chemical_list: D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; D051765:Early Growth Response Transcription Factors; D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors; C529571:ZFAT protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3